2005 Fiscal Year Final Research Report Summary
Elucidation of the molecular pathogenesis of dialysis-related amyloidosis.
| Project/Area Number |
15390123
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Experimental pathology
|
|---|
| Research Institution | University of Fukui (2004-2005)
福井医科大学 (2003) |
|---|
Principal Investigator |
NAIKI Hironobu University of Fukui, Faculty of Medical Sciences, Professor, 医学部, 教授 (10227704)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
HASEGAWA Kazuhiro University of Fukui, Faculty of Medical Sciences, Research Associate, 医学部, 助手 (60324159)
HIGUCHI Keiichi Shinshu University, Granduate School of Medicine, Professor, 大学院・医学研究科, 教授 (20173156)
|
|---|
| Project Period (FY) |
2003 – 2005
|
| Keywords | Amyloid fibril / Dialysis-related amyloidosis / Beta2-microglobulin / Trifluoroethanol / Glycosamonoglycans / Sodium dodecyl sulfate / Lysophospholipids / Transgenic mouse |
|---|
| Research Abstract |
β2-Microglobulin (β2-m)-related amyloidosis (dialysis-related amyloidosis, DRA) is a frequent and serious complication in patients on long-term dialysis, and β2-m is a major structural component of β2-m amyloid fibril (fAβ2M). The aims of this study are (1) establishment of molecular model of fAβ2M formation from β2-m monomer, (2) elucidation of the effect of various biological molecules or chemical compounds on the fibril formation and degradation, and on the pathogenesis of DRA, (3) proposition of a strategy for the treatment of DRA on the basis of molecular interaction investigated. For these purpose, we improved the previous in vitro amyloid fibril formation system and also developed a transgenic mouse for the model of DRA.
Results : In fAβ2M formation, partial unfolding of β2-m is believed to be prerequisite to its assembly into fibrils. (1) Trifluoroethanol (5-20%) was found to induce the amyloidogenic unfolding of β2-m and to stabilize the fibrils, resulted in the extension of fAβ2M at a neutral pH. In addition, some glycosamonoglycans enhanced the fibril extension probably by binding to the fibrils and stabilizing them. (2) At around the critical micelle concentration, sodium dodecyl sulfate, an analogue of phospholipids, was also found to induce the extension of fAβ2M by inducing the amyloidogenic unfolding of β2-m at a neutral pH. (3) Some anionic lysophospholipids were found to extend fAβ2M at a neutral pH in vitro. These are the first group of physiological agents, which may participate in the fibrillogenesis in the patients. (4) The human β2-m transgenic mice were successfully produced and confirmed that the levels of β2-m in the serum were elevated to several times higher than those of the patients on long-term dialysis.
As the conclusion of this study, the remarkable advance on the clarification of the molecular mechanism of fAβ2M formation in vitro, and on the production of transgenic mouse as a in vivo model system were obtained.
|
